Lassa Virus, ML-29 Vaccine:

Motivation and Background:

Lassa Hemorrhagic Fever (LASV) is a fever endemic to West Africa and a member of the Arenavirus family, which contain Luna (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia (SABV). The main vector are rodents which contaminate food or eaten or exposed to bodily fluid. The virus can be spread from human to human in all the same ways in addition to sexual and aerosol transmission. The arenaviruses range from 40 to over 200 nm and incorporate host ribosomes into their nucleocapsid giving the virus a sandy look. Within the capsid are 2 ambisense RNA strands, one long (7kb) and one short (3.4kb), which code for RNA polymerase (L) and zinc-binding protein (Z); and nucleoprotein (NP), glycoproteins 1 & 2 (GP) , and Stable Signal Peptide (SSP), respectively. L polymerase and NP work together to perform a “cap snatching” strategy, which removes the caps from host mRNA and switches them to viral RNA for replication and translation.
The ML-29 vaccine helps prime the immune antibodies for recognizing the NP and Z proteins. NP and Z both help suppress immune response and help in the the process of getting through the cell membrane. Due to the nature of the vaccine it can be used both to help treat the infected as well as prevent infection.

Figure 1: Lassa viruses are shown within cells of a culture. The viruses are seen as the grey bumpy dots within the circles. Their rough nature is a defining characteristic of arena viruses. Their rough capsid is reminiscent of sand and is the root of Arenavirus, a latin word meaning sand.

Figure 2: Cross section of the capsid of the virus showing both the short and long strand RNA, as well as the Glycoproteins which gives Arenaviruses their distinct look. The view shows how Z protein is embedded in the bilayer phospholipid, and shows where SSP would be (between glycoproteins).

References:
1.Carrion, R.; Bredenbeek, P.; Jiang, X.; Tretyakova, I.; Pushko, P.; Lukashevich, I. S., Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers. J Vaccines Vaccin 2012,3 (7).
2.Lukashevich, I. S.; Carrion, R.; Salvato, M. S.; Mansfield, K.; Brasky, K.; Zapata, J.; Cairo, C.; Goicochea, M.; Hoosien, G. E.; Ticer, A.; Bryant, J.; Davis, H.; Hammamieh, R.; Mayda, M.; Jett, M.; Patterson, J., Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates. Vaccine 2008,26 (41), 5246-54.
3.Meyer, B.; Ly, H., Inhibition of Innate Immune Responses Is Key to Pathogenesis by Arenaviruses. J Virol 2016,90 (8), 3810-8.
4.Yun, N. E.; Walker, D. H., Pathogenesis of Lassa fever. Viruses 2012,4 (10), 2031-48.
5.Zapata, J. C.; Carrion, R.; Patterson, J. L.; Crasta, O.; Zhang, Y.; Mani, S.; Jett, M.; Poonia, B.; Djavani, M.; White, D. M.; Lukashevich, I. S.; Salvato, M. S., Transcriptome analysis of human peripheral blood mononuclear cells exposed to Lassa virus and to the attenuated Mopeia/Lassa reassortant 29 (ML29), a vaccine candidate. PLoS Negl Trop Dis 2013,7 (9), e2406.

Target Information:

Weight: 63 Kilodaltons

Location: Surface membrane in capsid

Function in Virus: Suppress immune response and gain access to cell by receptor mediated entry

Drug Information:

Formula: Long Strand Short Strand

Molecular weight: 386.68 kilodaltons

Delivery method: Attenutated Vaccine
Side effects: None in non-human primates and guinea pigs

Origin: Modified 'clone' proteins inserted into an adapted Yellow Fever vaccine to use the premade mechanics of the replication of the other vaccine.

Alternatives the Drug:

Figure 3: List of Arenaviruses with their clinically tested vaccines. Those abbreviated as LASV are those for Lassa Virus. ML-29 is most promising but the lack of funding and rigorous testing for FDA approval makes it unlikely to be pushed into the US market.

Other uses: can this drug be used to treat other diseases/conditions?
The vaccine is much more than just a vaccine, in every experiment around Lassa Virus several other diseases are closer to having vaccines. The process of inserting new protein targets within YF vaccine would allow for near copy and paste effectiveness for other Arenaviruses. If successful it is a proof of concept for the emerging diseases like Sabia as well as old world endemic diseases.